The final common pathway of all these forms of infertility is the local accumulation of oxygen free radicals (Pasqualotto F. F. et al., Fertil. Steril. 73:459-464, 1999). To combat this accumulation antioxidant drugs can be used.
Most of the antioxidants currently available on the pharmaceutical market (vitamin E, glutathione, NADH) act in a manner unrelated to the Krebs cycle, and therefore in a manner related solely to the drug dosage and not to cell metabolism.
The substantial topographical and temporal heterogeneousness (within the same testicle) of human spermatogenesis (Silber S. J., Clin. Obstet. Gynaecol. 43:843-888, 1999) makes it impossible to establish a “fixed” dosage of antioxidants, since this would lead to over- and underdosing.
An excessive lowering of oxygen free radicals leads to inhibition of the acrosome and capacitation reaction of the spermatozoa (Ochendorf F. R., Hum. Reprod. Update. 5:399-402, 1999), whereas too high a concentration leads to morphological abnormalities of the spermatozoon itself (Gattuccio F., et. al., Varicocele 2000, Cofese Editore, Palermo 2000).
In Human Reprod. 13:3090-3093, 1998, a semiquantitative scoring system has been proposed based on US Doppler results to distinguish between obstructive and non-obstructive azoospermias.
In Human. Reprod. 15:2554-2558, 2000, it is reported that the transmediastinic testicular artery has a significantly greater resistivity index in non-obstructive azoospermic subjects than in controls and in oligoasthenospermic subjects.
In Fertil. Steril. 75:1088-1094, 2001, it is reported that the pulsatility index of the testicular artery is higher in obstructive than in non-obstructive azoospermia.
In J. Urol. 163:135, 2000, it is reported that intratesticular blood flow and blood flow rate are significantly lower in subjects with arrested maturation of spermatogenesis, that is to say with hypoplasia of the germ cells.
The spermatozoa are produced in the testicles and undergo post-gonadal maturation in the epididymis in order to acquire their fertilising capacity.
In plasma, high-molecular-weight proteins and small molecules such as the free carnitines facilitate the maturation of the gametes into competent, functional cells.
Epididymal L-carnitine, which comes from the plasma, has a beneficial effect on the spermatozoa. It passes into the spermatozoa by passive diffusion and is acetylated only in mature spermatozoa.
The relationship between the endogenous pool of free and acetylated carnitines and the progressive percentage of sperm motility indicate a more important metabolic function related to flagellar movement.
Thus, the start of sperm motility, in the epididymis, is probably independent of the carnitine system, while the energy properties of acetyl L-carnitine are relevant in “energy crisis” situations.
The accumulation of free carnitines in the cytoplasm in mature spermatozoa has to be regarded as a protective form of the mitochondrial metabolism which is useful for the survival of these isolated cells.
The use of L-carnitine, acetyl L-carnitine and propionyl L-carnitine in combination is already known.
In European patent EP 0 973 415, a dietetic composition is described consisting of L-carnitine, acetyl L-carnitine and propionyl L-carnitine, which is useful for athletes subject to intense physical effort, or for asthenic individuals.
In patent application WO 99/17623, a dietetic composition is described consisting of L-carnitine, acetyl L-carnitine and propionyl L-carnitine for the treatment of alcohol withdrawal syndrome.
Also known is the use of L-carnitine and of the alkanoyl L-carnitines for the treatment of male infertility.
In Drugs Exptl. Clin. Res. XXI(4):157-159, 1995, it is reported that the administration of L-carnitine, in a group of patients with idiopathic asthenospermia, improves sperm motility and increases the sperm count in 37 out of 47 patients treated.
In Dermatol. Monatschr. 169:572-575, 1983, the same results are confirmed.
In Andrologia, 26:155-159, 1994, it is reported that the administration of L-carnitine in infertile patients brings about a significant improvement of both a quantitative and qualitative nature in sperm motility.
In Fertilität 4.1-4, 1988, it is reported that L-carnitine therapy in infertile patients brings about an increase in carnitine levels in the spermatozoa and at the same time an increase in sperm motility and sperm count.
Loumbakis P., et al. (12th Congress of the European Association of Urology, Paris, 1-4 Sep., 1996) report preliminary data indicating that the administration of L-carnitine may have a positive effect on sperm quality.
In Acta Eur. Fertil. 23(5):221-224, 1992, it is reported that the use of acetyl L-carnitine in patients with idiopathic oligoastheno-spermia has no effect upon sperm density, but induces a progressive increase in sperm motility.
In U.S. Pat. No. 6,090,848, it is reported that the combination of L-carnitine and acetyl L-carnitine is useful for the treatment of oligoasthenoteratospermia.
The above-mentioned known compounds are certainly to be regarded as good therapeutic agents, but nevertheless present a number of disadvantages.
In fact, as mentioned above, in Drugs Exptl. Clin. Res. XXI (4):157-159, 1995, it is reported that the administration of L-carnitine to a group of patients with idiopathic oligoasthenoteratospermia improves the sperm count and increases sperm motility in 37 out of 47 patients treated, whereas, in Acta Eur. Fertil. 23(5):221-224, 1992, it is reported that the use of acetyl L-carnitine in patients with idiopathic oligoasthenospermia has no effect upon sperm density.
The combination described in U.S. Pat. No. 6,090,848, which is to be regarded as the best one known to date, was used as a reference compound during the study of the activity of the composition according to the present invention. The results obtained, reported here below, confirmed the activity of the composition described in U.S. Pat. No. 6,090,848, but also demonstrated, surprisingly and unexpectedly, that the combination according to the present invention is more active than the composition described in U.S. Pat. No. 6,090,848.
In the medical field, there is still a strongly perceived need for the availability of compositions useful for the treatment of oligoasthenoteratospermia, which do not present the disadvantages of the above-mentioned known compounds, or which improve the results obtained with the best of the known compositions currently in use.